The overall goal of this research program is to gain insight into the common cellular and molecular mechanisms through which reactive oxygen species (ROS) and inflammation individually and together mediate normal vascular function and vascular disease. While ROS are required for normal metabolic function and cell viability, excessive ROS or weakened antioxidant defenses can lead to pathophysiological events. Similarly, while monocytes and macrophages mediate healing and new vessel formation, excess inflammation contributes to atherosclerosis and hypertension. Over the past 25 years, our research group has investigated the myriad responses to ROS production and inflammation in the vasculature and studied their roles in virtually all of the major vascular diseases. In this proposal, we will expand upon these findings to better understand the mechanisms by which ROS and inflammation are both necessary and detrimental to vascular function, and to begin to explore therapeutic strategies for targeted intervention. In Project 1, Dr. Hanjoong Jo will explore the mechanisms responsible for, and consequences of, downregulation of bone morphogenic receptor II (BMPR2) by pro-atherogenic microRNAs and will develop target site blockers that can protect BMPR2 from downregulation. In Project 2, Dr. Aloke Finn will study a new type of non-foam cell macrophage, M(Hb) or Hb- associated macrophage, that expresses CD163. He will test the hypothesis that these novel macrophages induce plaque angiogenesis and increase macrophage survival, promoting the development of high-risk plaques. In Project 3, Dr. Kathy Griendling will examine the functional and structural aspects of the Nox4- associated protein, Poldip2, that contribute to matrix regulation and aortic stiffening, and will tst targeted therapeutic strategies to prevent aneurysm formation. Dr. Alejandra San Martin is also studying Poldip2 in Project 4, but with an eye to understanding its role in mitochondrial dynamics and proliferation. Finally, in Project 5, Dr. W. Robert Taylor will investigate how the expression of catalase, a critically important antioxidant enzyme that modulates wall stiffness and aneurysm formation, is regulated by the PGC-1a pathway or polymorphisms, and will test inhibitors of catalase expression for their efficacy in treating aneurysms. The proposed studies will be supported by the exceptional collaborative expertise of Dr. Lula Hilenski, the director of the Microscopy in Medicine Core, and Dr. Bernard Lassgue, director of the Animal Core. While the major goal of the program is centered on understanding basic mechanisms of disease and beginning to translate them into clinically relevant applications, we are also dedicated to trainin the next generation of investigators, supporting the careers of junior faculty, and disseminating our findings to serve as a nidus for future investigation. This PPG application thus represents a distinctive multidisciplinary collaboration among highly qualified scientists with extensive experience in oxidative stress, inflammation and vascular biology who remain committed to defining the pathophysiologic basis of vascular disease.